Bottom Line:
Functional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins.Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors.These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.

Affiliation: Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.

ABSTRACTFunctional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors. TARPs exhibit discrete and complementary patterns of expression in both neurons and glia in the developing and mature central nervous system. In brain regions that express multiple isoforms, such as cerebral cortex, TARP-AMPA receptor complexes are strictly segregated, suggesting distinct roles for TARP isoforms. TARPs interact with AMPA receptors at the postsynaptic density, and surface expression of mature AMPA receptors requires a TARP. These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.

fig4: Developmental switch in neuronal expression of TARPs. Immunoblotting shows that γ-4 protein levels peak in rat pups at postnatal day 6 (P6) and decline thereafter in cerebral cortex. In contrast, expression of stargazin (STG), γ-3, and γ-8 appear later and progressively increase during animal maturation. In situ hybridization at embryonic day 16 (E16) shows that γ-4 mRNA but not that of other TARPs occurs at extremely high levels throughout the nervous system in cortical plate (CP), olfactory epithelium (OE), dorsal root ganglia (DRG), and spinal cord (SC). Some γ-4 mRNA also occurs in peripheral tissues such as the intestine (IN).

Mentions:
We also explored the developmental course of TARP expression during rat ontogeny. Western blotting of brain cerebral cortex homogenates shows that γ-2, γ-3, and γ-8 are expressed at low levels in newborn and neonatal brain and increase to reach highest levels in adult (Fig. 4 A). By contrast, γ-4 expression peaks at postnatal day 6 and decreases through later development. In situ hybridization confirmed the robust expression of γ-4 but not other TARPs in E16 embryo (Fig. 4 B). High levels of γ-4 expression occur in neurons throughout the developing central and peripheral nervous systems. Some expression of γ-4 is found also in nonneuronal cells, such as epithelial cells lining the intestines (Fig. 4 B), but γ-4 is absent from most peripheral tissues.

fig4: Developmental switch in neuronal expression of TARPs. Immunoblotting shows that γ-4 protein levels peak in rat pups at postnatal day 6 (P6) and decline thereafter in cerebral cortex. In contrast, expression of stargazin (STG), γ-3, and γ-8 appear later and progressively increase during animal maturation. In situ hybridization at embryonic day 16 (E16) shows that γ-4 mRNA but not that of other TARPs occurs at extremely high levels throughout the nervous system in cortical plate (CP), olfactory epithelium (OE), dorsal root ganglia (DRG), and spinal cord (SC). Some γ-4 mRNA also occurs in peripheral tissues such as the intestine (IN).

Mentions:
We also explored the developmental course of TARP expression during rat ontogeny. Western blotting of brain cerebral cortex homogenates shows that γ-2, γ-3, and γ-8 are expressed at low levels in newborn and neonatal brain and increase to reach highest levels in adult (Fig. 4 A). By contrast, γ-4 expression peaks at postnatal day 6 and decreases through later development. In situ hybridization confirmed the robust expression of γ-4 but not other TARPs in E16 embryo (Fig. 4 B). High levels of γ-4 expression occur in neurons throughout the developing central and peripheral nervous systems. Some expression of γ-4 is found also in nonneuronal cells, such as epithelial cells lining the intestines (Fig. 4 B), but γ-4 is absent from most peripheral tissues.

Bottom Line:
Functional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins.Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors.These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.

Affiliation:
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.

ABSTRACTFunctional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors. TARPs exhibit discrete and complementary patterns of expression in both neurons and glia in the developing and mature central nervous system. In brain regions that express multiple isoforms, such as cerebral cortex, TARP-AMPA receptor complexes are strictly segregated, suggesting distinct roles for TARP isoforms. TARPs interact with AMPA receptors at the postsynaptic density, and surface expression of mature AMPA receptors requires a TARP. These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.